Download Non-steroidal anti- inflammatory drugs (NSAIDs)

Non-steroidal antiinflammatory drugs
(NSAIDs)
R. B. Janani Buddhika
Dept. of Health Sciences
The Open University of Sri Lanka
Non-Steroidal Anti-inflammatory Drugs
(NSAIDs)
Used in mild to moderate pain
Provide symptomatic relief from pain & swelling in,
• chronic joint disease - osteo- & rheumatoid
arthritis
• acute inflammatory conditions - sport injuries
fractures, sprains & other soft tissue injuries
• postoperative pains
• dental & menstrual pain
• pain of headaches & migraine
(NSAIDs) cont.
• Often taken without prescription for other types of
minor aches & pains
• Different formulations -tablets, injections, gels
• All NSAIDs, particularly the 'classic' NSAIDs, can
have significant unwanted effects- especially in
elderly
• Newer agents- fewer adverse actions
MECHANISM OF
ACTION OF NSAIDs
NSAIDs - Mechanism of action
• NSAIDs are inhibitors of cyclooxygenase
• Most NSAIDs inhibit both cox1 & cox2 iso
enzymes
• Cyclooxygenases catalyse the formation of
prostaglandins (PG) & thromboxanes from
arachidonic acid
• Therefore NSAIDs inhibit the formation of
prostaglandins & thromboxanes (TX) from
arachidonic acid
NSAIDs - Mechanism of action cont.
• Reduced synthesis of PGE2 & PGF2 is associated
with their anti inflammatory action
• Reduced thromboxane synthesis is associated with
platelet aggregation & adhesiveness
• NSAIDs does not inhibit lipoxygenase
• NSAIDs does not alter production of leukotrienes
Membrane phospholipids
For
Maintenance
Arachidonic acid
COX-1
In Induced
situations
COX-2
NSAIDs
thromboxane / prostaglandins
Primarily support
platelet function
Primarily protect
GI mucosa
Coxibs
prostaglandins
Primarily mediate
inflammation, pain & fever
NSAIDs - Mechanism of action cont.
• Aspirin and traditional NSAIDs inhibit both COX 1 &
COX 2
Prostaglandin
• Local hormones produced in body, have diverse effects in
the body
• Transmit pain information to the brain
• Modulate hypothalamic thermostat & inflammation
Thromboxane
Responsible for aggregation of platelets from blood clots
For understanding the concept…
Prostaglandins, & the related compounds
thromboxanes & leukotrienes
• collectively known as eicosanoids to reflect their origin
•
•
•
•
•
from polyunsaturated fatty acids with 20 carbons
extremely potent compounds that elicit a wide range of
responses, both physiologic & pathologic
produced in very small amounts in almost all tissues
rather than in specialized glands
act locally
not stored
short half-life as rapidly metabolized to inactive products
For understanding the concept…
Inhibition of prostaglandin synthesis
by a number of unrelated compounds
• Cortisol (a steroidal anti-inflammatory agent)
• inhibit phospholipase A2 activity (therefore arachidonic acid,
precursor of the prostaglandins,is not available)
• NSAIDS
• inhibit both COX-1 and COX-2 and, therefore, prevent the
synthesis of the parent prostaglandin, PGH2.
• [Note: Systemic inhibition of COX-1, with subsequent damage to
the stomach and the kidneys, and impaired clotting of blood, is the
basis of aspirin's toxicity.]
• Inhibitors specific for COX-2 (for example, celecoxib)
• reduce pathologic inflammatory processes while maintaining the
physiologic functions of COX-1; however, their use has been
associated with increased risk of heart attacks.
COX-1
– (synthesized in normal physiological conditions)
• a constitutive enzyme
(constantly produced by cells)
• expressed in most tissues (esp. GI, kidneys,
endothelial cells) & blood platelets
• COX-1 required for
• maintenance of healthy gastric tissue
• renal homeostasis
• platelet aggregation
• required for maintenance of tissue homeostasis
• initiation of delivery
COX-2
- (synthesized especially in pathological
conditions)
• found in brain, bone, kidneys, GI tract, & the
female reproductive system
• responsible for production of prostanoid
mediators of inflammation
• COX-2 - inducible in a limited number of tissues
in response to products of activated immune &
inflammatory cells
• increase in prostaglandin synthesis subsequent to the
induction of COX-2 mediates the pain, heat, redness, &
swelling of inflammation, & the fever of infection.
COX-3
• Discovered in 2002.
PHARMACOKINETICS
Pharmacokinetics
• Most NSAIDs are weak acids
• Well absorbed from the stomach & intestinal
mucosa
• Do not undergo 1st pass metabolism
• Highly plama protein bound(>95%) – usually to
albumin.
• Vd small
• Most NSAIDs are metabolised in liver
• By oxidation & conjugation to inactive metaboiltes
• Excreted in urine
PHARMACOLOGICAL
ACTIONS
Pharmacological actions NSAIDs
3 major pharmacologically desirable actions,
An anti-inflammatory action:
• Decrease in prostaglandin E2 & prostacyclin reduces vasodilatation
&, indirectly, oedema
• Accumulation of inflammatory cells is not reduced
An analgesic effect:
• Decrease prostaglandin generation means less sensitisation of
nociceptive nerve endings to inflammatory mediators such as
bradykinin and 5-hydroxytryptamine
• Relief of headache by decreasing prostaglandin-mediated
vasodilatation
Pharmacological actions NSAIDs cont.
An antipyretic effect:
interleukin-1 releases prostaglandins in the CNS, where
they elevate the hypothalamic set point for temperature
control causing fever. NSAIDs prevent this.
Pharmacological actions NSAIDs cont.
• In addition to the desirable pharmacological effects, all the
NSAIDs have, to a greater or lesser degree, the same
types of mechanism-based side effects.
• gastric irritation- from simple discomfort to ulcer
formation
• effect on renal blood flow in the compromised kidney
• tendency to prolong bleeding - by inhibition of platelet
function
Clinical uses of NSAIDs
• For analgesia
• e.g. headache, dysmenorrhoea, backache, postoperative pain
• Short-term use- Aspirin, paracetamol or ibuprofen
• Chronic pain: more potent, longer lasting drugs e.g. naproxen,
piroxicam
• To reduce the requirement for narcotic analgesics e.g.
ketorolac postoperatively
• To lower temperature (antipyretic): paracetamol
• For anti-inflammatory effects
• e.g. rheumatoid arthritis and related connective tissue disorders,
gout & soft tissue disorders
Note -there is substantial individual variation in clinical
response to NSAIDs and considerable unpredictable
patient preference for one drug rather than another.
ADVERSE EFFECTS
Unwanted effects of NSAIDs
• By inhibition of the constitutive housekeeping enzyme
cyclo-oxygenase (COX)-1 isoform of COX, are common,
particularly in the elderly
1. Gastrointestinal Side Effects- Dyspepsia, nausea &
vomiting.
• Gastric damage - chronic users, with risk of haemorrhage. The
cause is suppression of gastroprotective prostaglandins in the
gastric mucosa.
2. Reversible renal insufficiency.
• When the compensatory prostaglandin E2-mediated vasodilatation is
inhibited.
3. Skin reactions. Mechanism unknown.
Unwanted effects of NSAIDs cont.
4. 'Analgesic-associated nephropathy'.
• Due to long-continued high doses of NSAIDs (e.g. paracetamol) and is
often irreversible.
5. Liver disorders, bone marrow depression. Relatively
uncommon.
6. Bronchospasm - in 'aspirin-sensitive' asthmatics.
1. GI side effects
• Commonest side effect of NSAIDs
• Inhibition of gastric COX-1, responsible for synthesis of
prostaglandins that normally inhibit acid secretion &
protect the mucosa
• Common GI side effects,
• gastric discomfort, dyspepsia, diarrhoea, nausea & vomiting,
gastric bleeding and ulceration
• Oral administration of prostaglandin analogues
(misoprostol) can diminish gastric damage produced by
NSAIDs.
2. Renal side effects
• Therapeutic doses in,
• Healthy individuals - little threat to kidney function
• Susceptible patients - cause acute renal insufficiency, reversible on
stopping the drug
• NSAIDs inhibit biosynthesis of prostanoids (PGE2 &
PGI2; prostacyclin).
• Prostaglandins (esp. PGE2 ) normally cause vasodilation of
afferent arterioles of glomeruli
• This helps to maintain normal glomerular perfusion & glomerular
filtration rate (GFR)
• NSAIDs block this effect and may cause renal impairment.
2. Renal side effects cont.
• Patients at risk
• Neonates & elderly
• Patients with heart, liver or kidney disease , or a reduced circulating
blood volume
• Chronic NSAIDs consumption
• May cause analgesic nephropathy characterized by chronic
nephritis and renal papillary necrosis
NSAIDs in Pregnancy & Lactation
• Contra-indicated during pregnancy, labour & delivery esp.
ketorolac (particularly in 3rd trimester)
• May cause closure of ductus arteriosus & impaired fetal
circulation
• Use of NSAIDs & aspirin late in pregnancy may increase
the risk of postpartum hemorrhage.
Drug Interactions
• Concomitant NSAIDs & Low-Dose Aspirin
• Classic NSAIDs or COX-2 inhibitors with "cardioprotective" lowdose aspirin may increase the likelihood of GI adverse effects.
• This interaction should not occur with selective COX-2 inhibitors,
because mature human platelets lack COX-2.
Other Drug Interactions
• NSAIDs & ACEI
• NSAIDs may reduce the effectiveness of ACE inhibitors by blocking
the production of vasodilator & natriuretic prostaglandins.
• Can produce marked bradycardia
• NSAIDs & corticosteroids
• May increase the frequency or severity of GI ulceration
Drug Interactions cont.
• NSAIDs & warfarin
• Increase the risk of bleeding
• NSAIDs & high plasma protein bound drugs
• Many NSAIDs are highly bound to plasma proteins and thus may
displace other drugs from their binding sites.
• Dose of such agents may require to adjust to prevent toxicity
SOME IMPORTANT
NSAIDS
Cyclo-oxygenase-inhibitory specificity of some
common non-steroidal anti-inflammatory drugs &
coxibs
COX-1
Non
selective
COX-2
Group
Examples
Highly COX-1-selective
Ketorolac
Weakly COX-1selective
Indometacin, aspirin , naproxen,
ibuprofen
Non-selective; full
inhibition of both
enzymes
Fenoprofen
Non-selective;
incomplete inhibition
of both enzymes
Salicylate
Weakly COX-2selective
Diflunisal, piroxicam, meclofenamate,
diclofenac, celecoxib
Very COX-2-selective
Valdecoxib, etoricoxib
Aspirin (acetylsalicylic acid)
• Oldest non-steroidal anti-inflammatory drug
• Irreversibly inactivate both cyclo-oxygenase (COX)-1 &
COX-2
• anti-inflammatory action
• inhibits platelet aggregation
• main clinical importance -in the therapy of myocardial infarction
Aspirin – Pharmacokinetics
• It is given orally and is rapidly absorbed;
• 75% is metabolised in liver
• Elimination follows first-order kinetics with low doses (half-
life 4 hours), and saturation kinetics with high doses (halflife over 15 hours)
Aspirin - MOA
Mechanism of action
• Irreversibly inactivate cox enzymes.
• Aspirin irreversibly inhibits cox1 and modifies the
enzymatic activity of cox2
Aspirin acts as an acetylating agent and it covalently
attaches its acetyl group to serine residue in the active
site of the cox enzyme.
This makes aspirin different from other NSAIDs (such as diclofenac and
Ibuprofen which are reversible inhibitors)
Aspirin (acetylsalicylic acid) cont.
Unwanted effects
• with therapeutic doses: some gastric bleeding
• with large doses: dizziness, deafness & tinnitus
('salicylism'); compensated respiratory alkalosis may
occur
• with toxic doses (e.g. from self-poisoning):
uncompensated respiratory acidosis with metabolic
acidosis may occur,
• in children - Reye's syndrome
• concomitant use with warfarin, can cause a potentially
hazardous increase in the risk of bleeding
PARACETAMOL
Paracetamol
• Has potent analgesic and antipyretic actions
• Weaker anti-inflammatory effects than other NSAIDs.
• May act through inhibition of a central nervous system-
specific cyclo-oxygenase (COX) isoform such as COX-3,
although this is not yet conclusive.
• Given orally
• Metabolised in the liver (half-life 2-4 hours).
Paracetamol cont.
• Toxic doses -cause nausea and vomiting
• after 24-48 hours-potentially fatal liver damage by saturating
normal conjugating enzymes, causing the drug to be converted by
mixed function oxidases to N-acetyl-p-benzoquinone imine. If not
inactivated by conjugation with glutathione, this compound reacts
with cell proteins and kills the cell.
• Agents that increase glutathione (intravenous acetylcysteine or oral
methionine) can prevent liver damage if given early.
Agents selective for cyclo-oxygenase-2
Eg. Celecoxib, etoricoxib
• Several have been withdrawn, & overall licensing situation
is volatile
• Current advice restricts the use of coxibs to patients for
whom treatment with conventional NSAIDs would pose a
high probability of serious gastrointestinal side effects,
and
• Coxibs are adviced to prescribed only after an
assessment of cardiovascular risk
Other NSAIDs
• Indomethacin
• Diclofenac
• Ibuprofen
• Mefanamic acid
Indomethacin
• Prominent antiinflammatory & analgesic-antipyretic
properties similar to those of the salicylates (as asprin)
• More potent inhibitor of the cyclooxygenases than is
aspirin
• but patient intolerance generally limits its use to short-term dosing
• Inhibits the motility of polymorphonuclear leukocytes &
depresses the biosynthesis of mucopolysaccharides
• Uses - relieving joint pain, swelling, & tenderness,
increasing grip strength
Diclofenac
• Analgesic, antipyretic, & antiinflammatory effect
• Potency against COX-2 is greater than that of
indomethacin, naproxen, or several other classic NSAIDs
• Reduce intracellular concentrations of free AA in
leukocytes
• Selectivity of diclofenac for COX-2 resembles that of
celecoxib
Oxicams- Enolic Acids
Eg. Piroxicam, Meloxicam
• Inhibit COX-1 and COX-2
• Have anti-inflammatory, analgesic,& antipyretic activity
• Generally nonselective COX inhibitors
• But one member (meloxicam) shows modest COX-2
selectivity comparable to celecoxib
• Similar in efficacy to aspirin, indomethacin, or naproxen
for the long-term treatment of rheumatoid arthritis or
osteoarthritis
• Long half-life - once-a-day dosing
References:
1. Pharmacology by M. P. Rang, M. M. Dale, & J. M. Ritter.
2. Goodman and Gilman 11th edition
Thank you